In Alzheimer's Disease (AD), the cleavage of beta amyloid protein precursor from the intracellular membrane often produces a protein AB-42 which is incompletely removed by normal clearance processes. Over time, this protein is deposited as a beta amyloid protein (Aβ) plaque within brain tissue, leading to the local destruction of neurons. The Aβ plaque deposition is also believed to provoke an inflammatory response by microglia and macrophages. These cells are believed to respond to the plaque deposition by releasing pro-inflammatory cytokines and reactive oxygen species (ROS). Although the inflammatory response may be provoked in an effort to clear the brain tissue of the detrimental plaque, it is now believed that this inflammation also injures local neuronal tissue, thereby exacerbating AD.
Now referring to FIG. 1, in most AD cases, the progression of AD begins in the hippocampus, wherein the patient suffers a loss of short term memory. From the hippocampus, the disease spreads to the amydgala, and then proceeds anteriorly to the prefrontal cortex. Since the prefrontal cortex controls problem-solving, a person suffering from AD begins to lose their ability to learn when the disease affects the prefrontal cortex. In general, impairment of the prefrontal cortex begins to appear a few years after loss of short-term memory.
The olfactory bulb (OB) is located just above the top of the nasal cavity and is intimately involved in the sense of smell. Olfactory nerve fibers located in the nasal cavity extend through the cribriform plate and enter the OB along its longitudinal axis. The OB projects through the lateral olfactory tracts to the olfactory tubercles, the pyriform cortex, the cortical amydgala nucleus and the ventrolateral entorhinal area.
There is substantial evidence that the OB is one of the first portions of the brain affected by AD. Davies, Neurobiol. Aging, 1993, July-August 14(4) 353-7. Investigators have found significant early tau-related pathology in the OB of AD patients. Tsuboi, Neurpathol., Appl. Neurobiol. 2003, October 29(5) 503-10. Increased numbers of neuritic plaques and neurofibrillary tangles on the OB have been demonstrated in AD patients. Yamamoto, Yakunutsu Seishin Kodo, August 11(4), 223-35.
In addition to its olfactory functions, the OB is particularly rich in acetylcholine and other neurotransmitters and delivers these neurotransmitters to other portions of the brain. Since the OB is well interconnected within the brain, destruction of the OB by AD may well lead to accelerated destruction of other portions of the AD brain. Some investigators have suggested that neural injury to the OB may result in collateral damage to other limbs of the cholinergic system. For example, it has been found that lesioning of the OB results in severely reduced expression of BDNF expression in an afferent structure, the hlDBB, and reduced choline uptake and ChAT activity locally and in the cingulated cortex. Sohrabji, J. Neurobiol., 2000, Nov. 5, 45(2) 61-74. Some investigators have found that the most severely affected areas of the AD brain are interconnected with the central olfactory system in contrast to the relative sparing of the other sensory areas which lack olfactory connection. Kovacs, Neurpathol., Appl. Neurobiol., 1999, December 25(6) 481-91.
Indeed, many investigators have reported that olfactory bulbectomy leads to severe impairment in memory or learning. Yamamoto, Yakunutsu Seishin Kodo, August 11(4), 223-35; Yamamoto, Behav. Brain. Res. 1997, February 83(1-2) 57-62; Hozumi, Behav. Brain Res. 2003, Jan. 6, 138(1) 9-15; and Hallam, Behav. Brain Res. 2004, Aug. 31, 153(2):481-6. Hallam, supra, and Hozumi, supra, have tied this collateral deficit to impairment of the cholinergic system. Other investigators have suggested that bulbectomy initiates in the brain a pathological process similar to human Alzheimer's Disease in location, biochemistry and behavioural manifestations. Aleksandrova, Biochemistry (Mosc), 2004, February 69(2) 176-180.
A minority of investigators have even proposed that AD may begin in the OB due to pathogens entering via peripheral olfactory apparatus. Mann, Mech. Ageing Dev., 1988, January 42(1) 1-15. It has also been reported that neurofibrillary tangles spread from the entorhinal cortex to the limbic system, then to cortical areas, according to Braak's stages. Kovacs, Neuroreport. 2001, Feb. 12, 12(2) 285-8. However, these hypotheses have been disputed. See Davies, supra and Kovacs, Neuroreport. 2001, Feb. 12, 12(2) 285-8.
In sum, because the olfactory bulb plays a key role in the cholinergic system in the cerebral cortex, damage to the olfactory bulb not only impairs the patient's sense of smell, it also impairs vital systems related to learning and memory due to disruption of the cholinergic systems.
Because of the role played in AD by inflammation, anti-inflammatory compounds have been identified as candidates for treating Alzheimer's Disease. However, the delivery of these compounds has generally been through an oral route, and the systemic side effects associated with long term use of these compounds are often undesirable.
Some investigators have proposed implanting an effective amount of nerve growth factor (NGF) in a sustained release device for treating Alzheimer's Disease. However, NGF simply helps restore damaged neurons—it does little to stop the damage from occurring.
Other have examined the possibility of intranasal installation of therapeutic peptides in the form of drops. However, it is not known whether significant amounts of these peptides are able to cross through the nasal mucosa and into the cerebral cortex.